A Systems Biology Approach to HIV-associated Neurocognitive Impairment: Role of Drug Abuse and Neuroinflammation

HIV 相关神经认知障碍的系统生物学方法：药物滥用和神经炎症的作用

基本信息

批准号：
9344570
负责人：
CHRISTINA S MEADE
金额：
$ 72.18万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9344570
关键词：
Acquired Immunodeficiency Syndrome Address Adult Adverse effects Affect Alcohol or Other Drugs use American Anti-Inflammatory Agents Anti-inflammatory Attenuated Behavioral Biological Biology Blood - brain barrier anatomy Brain Brain imaging CCL2 gene Cannabinoids Cerebrospinal Fluid Cerebrum Clinical Cocaine Cocaine Users Collaborations Comorbidity Complex Computational Biology Computer Simulation Corpus Callosum Data Data Set Development Drug Addiction Drug abuse Exhibits Fostering Funding HIV HIV Infections HLA-DR Antigens High Prevalence Illicit Drugs Immune Immune System Diseases Immune System and Related Disorders Immunologics Immunology Impaired cognition Infiltration Inflammation Inflammatory Interleukin-6 Intervention Investigation Joints K-Series Research Career Programs Lead Leukocytes Link Macrophage Activation Magnetic Resonance Imaging Marijuana Measures Memory Modality Morbidity - disease rate Neopterin Neurocognition Neurocognitive Deficit Neurologic Neurophysiology - biologic function Neuropsychological Tests Neurosciences Outcome Parietal Pathogenesis Pathogenicity Pathway interactions Patients Pattern Peripheral Persons Pharmaceutical Preparations Play Process Production Research Research Personnel Role Sampling Science Structure Substance abuse problem System Systems Biology T-Lymphocyte TNF gene Testing Therapeutic United States National Institutes of Health Vascular Permeabilities Work antiretroviral therapy behavior measurement biological systems cocaine use cognitive function daily functioning drug of abuse executive function experience immune function immunoregulation innovation insight marijuana use marijuana user monocyte mortality multidisciplinary neurobehavioral neurocognitive test neurofilament neuroimaging neuroinflammation new therapeutic target non-drug novel predictive modeling processing speed programs public health relevance relating to nervous system sound time use transmission process white matter

项目摘要

Project Summary Even in the era of widespread combination antiretroviral therapy, over half of HIV-infected patients experience HIV-associated neurocognitive impairment (NCI). NCI is driven in part by persistent neuro- inflammation with activated monocytes and T cells playing pathogenic roles. Marijuana and cocaine, two of the mostly commonly abused drugs among HIV-infected persons, cause alterations in neural and cognitive functioning, and have significant immunomodulatory effects. While the effects of HIV infection and drug abuse on immune dysfunction and inflammation, brain structure/function, and NCI have been independently studied, the complex interactions between these biological systems are poorly characterized. Our preliminary work suggests that cocaine and marijuana use have discordant effects on NCI in persons with HIV, with differential impacts across domains of cognitive function. In addition, research has shown that stimulants like cocaine induce an activated immune state, whereas marijuana has anti-inflammatory effects. Building on the prior work of our multi-disciplinary team, with complementary expertise in neuroscience, drug addiction, HIV immunology, and computational biology, the proposed research uses a systems biology approach to investigate the effects of cocaine and marijuana on immune function, brain structure/function, and neurocognition in HIV-infected persons. We aim to: (1) identify the independent and joint effects of cocaine and marijuana use on MRI measures of cerebral volume, white matter integrity, and functional connectivity, and on behavioral measures of neurocognition; (2) quantify differences in peripheral and CNS immune function between marijuana and cocaine users; and (3) employ a systems biology approach to integrate immunology, neuroimaging, and behavioral data into a multi-level predictive model. Our guiding hypothesis is that cocaine induces an immune activated state that causes alterations in brain structure/function and cognitive impairment, while marijuana attenuates these effects through anti-inflammatory processes. The sample will include 150 adults with HIV infection who use cocaine only, marijuana only, cocaine and marijuana, or neither drug, comprising 4 distinct groups (~37/group). At study completion, we will have produced a comprehensive, multi-disciplinary dataset, and our systems biology approach will provide significant insights to generate novel hypotheses for future research on the complex biological intersection of HIV and substance use. This proposal addresses both a critical need to identify “factors that impact differences in neurocognitive impairment in association with specific patterns of substance abuse” [RFA-DA-16-013] and multiple high priority topics for AIDS-designated funding, including investigation of HIV-associated comorbidities such as neurological complications and understanding the basic biology of immune dysfunction and HIV transmission [NOT-15-137]. This innovative project has strong potential to elucidate the complex biological mechanisms through which HIV infection and drug abuse impact NCI, and to identify appropriate targets for novel therapeutics and clinical interventions.

项目概要即使在广泛联合抗逆转录病毒治疗的时代，超过一半的艾滋病毒感染者经历艾滋病毒相关的神经认知障碍（NCI）部分是由持续性神经认知障碍引起的。激活的单核细胞和 T 细胞在炎症中发挥致病作用，大麻和可卡因是其中的两种。 HIV感染者最常滥用的药物，会导致神经和认知的改变功能，并具有显着的免疫调节作用，同时对艾滋病毒感染和药物滥用的影响。关于免疫功能障碍和炎症、脑结构/功能和 NCI 的研究已被独立研究，我们的初步工作对这些生物系统之间复杂的相互作用的描述很差。表明可卡因和大麻的使用对 HIV 感染者的 NCI 具有不一致的影响，并且存在差异此外，研究表明可卡因等兴奋剂会对认知功能产生影响。诱导激活的免疫状态，而大麻具有抗炎作用。我们的多学科团队在神经科学、毒瘾、艾滋病毒免疫学等方面具有互补的专业知识，和计算生物学，拟议的研究使用系统生物学方法来研究其影响可卡因和大麻对艾滋病毒感染者的免疫功能、大脑结构/功能和神经认知的影响我们的目标是：(1) 确定可卡因和大麻使用对 MRI 的独立和联合影响。大脑容量、白质完整性、功能连接性以及行为测量的测量神经认知的影响；（2）量化大麻和中枢神经系统免疫功能的差异可卡因使用者；(3) 采用系统生物学方法整合免疫学、神经影像学和我们的指导假设是可卡因会诱导免疫。激活状态会导致大脑结构/功能改变和认知障碍，而大麻通过抗炎过程减弱这些影响该样本将包括 150 名感染艾滋病毒的成年人。仅使用可卡因、仅使用大麻、可卡因和大麻或两者都不使用的感染者，包括 4 种不同的药物组（约 37 个/组）。研究完成后，我们将生成一个全面的、多学科的数据集，我们的系统生物学方法将为未来产生新的假设提供重要的见解该提案涉及艾滋病毒和药物滥用之间复杂的生物学交叉点。迫切需要确定“影响与特定神经认知障碍相关的差异的因素” 药物滥用模式”[RFA-DA-16-013] 以及艾滋病指定资金的多个高度优先主题，包括对艾滋病毒相关合并症（如神经系统并发症）的调查和了解免疫功能障碍和 HIV 传播的基本生物学 [NOT-15-137]。阐明艾滋病毒感染和药物滥用的复杂生物学机制的巨大潜力影响 NCI，并确定新疗法和临床干预的适当目标。